Variant 21-36744738-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005069.6(SIM2):c.1178C>T(p.Ser393Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000639 in 1,602,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 1 hom. )

Consequence

SIM2
NM_005069.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.93

Variant links:

Genes affected

SIM2 (HGNC:10883): (SIM bHLH transcription factor 2) This gene represents a homolog of the Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of neurogenesis. The encoded protein is ubiquitinated by RING-IBR-RING-type E3 ubiquitin ligases, including the parkin RBR E3 ubiquitin protein ligase. This gene maps within the so-called Down syndrome chromosomal region, and is thus thought to contribute to some specific Down syndrome phenotypes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

SIM2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062109917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SIM2	NM_005069.6 linkuse as main transcript	c.1178C>T	p.Ser393Leu	missense_variant	10/11	ENST00000290399.11
SIM2	NM_009586.5 linkuse as main transcript	c.1178C>T	p.Ser393Leu	missense_variant	10/10
SIM2	XM_011529694.2 linkuse as main transcript	c.875C>T	p.Ser292Leu	missense_variant	9/10
SIM2	XM_047440952.1 linkuse as main transcript	c.875C>T	p.Ser292Leu	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM2	ENST00000290399.11 linkuse as main transcript	c.1178C>T	p.Ser393Leu	missense_variant	10/11	1	NM_005069.6	P1	Q14190-1
SIM2	ENST00000431229.1 linkuse as main transcript	c.992C>T	p.Ser331Leu	missense_variant	9/10	1
SIM2	ENST00000481185.1 linkuse as main transcript	n.1791C>T		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000334

AC:

AN:

230434

Hom.:

AF XY:

0.000354

AC XY:

AN XY:

124354

show subpopulations

Gnomad AFR exome

AF:

0.000139

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000662

AC:

960

AN:

1449898

Hom.:

Cov.:

AF XY:

0.000661

AC XY:

476

AN XY:

720044

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.0000380

Gnomad4 NFE exome

AF:

0.000841

Gnomad4 OTH exome

AF:

0.000366

GnomAD4 genome

AF:

0.000414

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000818

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000321

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1178C>T (p.S393L) alteration is located in exon 10 (coding exon 10) of the SIM2 gene. This alteration results from a C to T substitution at nucleotide position 1178, causing the serine (S) at amino acid position 393 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.12

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

M_CAP

Benign

0.020

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.56

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

REVEL

Benign

0.10

Sift

Benign

0.22

Sift4G

Benign

0.34

Polyphen

0.026

Vest4

0.20

MVP

0.62

MPC

0.27

ClinPred

0.11

GERP RS

4.2

Varity_R

0.22

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over